The spirocyclic derivatives of the present invention are inhibitors of human dopamine active transporter protein (DAT) and have a number of therapeutic applications, particularly in the treatment of sexual dysfunction, affective disorders, anxiety, depression, chronic fatigue, Tourette syndrome, Angelman syndrome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), obesity, pain, obsessive-compulsive disorder, movement disorders, CNS disorders, sleep disorders, narcolepsy, conduct disorder, substance abuse (including smoking cessation), eating disorders, and impulse control disorders.
Dopamine (DA) is a neurotransmitter which has a fundamental role in cognitive, affective, motor, motivational and reward-related functions. Following evoked action potentials DA is released into the synaptic cleft and this DA signal is extinguished by reuptake of DA into pre-synaptic neurons by DAT and by amine diffusion and local metabolism via enzymatic degradation. Dysfunction of the dopaminergic system is implicated in numerous CNS disorders and consequently DAT has been the focus of research into a number of these conditions and strong associations exist between abnormal DAT expression and/or function and disease.
Several marketed drugs have pharmacological activity at DAT, but none are selective and potent DAT inhibitors. Stimulants such as amphetamine and methylphenidate have multiple pharmacological activities including effects on synaptic levels of DA, noradrenaline (NE) and serotonin (5-HT). Despite their therapeutic potential in conditions such as ADHD, they also carry unwanted side effects such as abuse potential (1), cardiovascular effects (2), appetite suppression (3) and sleep disturbance (4).
Other non-selective DAT inhibitors are also used to treat CNS disorders. Bupropion which is prescribed as an antidepressant and a smoking cessation aid has a significant DAT component to its pharmacological activity, although it carries an increased seizure risk. Similarly Modafinil which is prescribed as a treatment for narcolepsy, excessive daytime sleepiness and shift work sleep disorder has been shown to inhibit DAT as part of its pharmacological mechanism of action. Multiple compounds have been developed that target the other monoamine transporters either selectively as inhibitors of the serotonin transporter (SERT) (Citalopram, Fluoxetine) or noradrenaline transporter (NET) inhibitors (Atomoxetine, Reboxetine) as well as dual serotonin/noradrenaline reuptake inhibitors (Venlafaxine). Drugs that inhibit SERT and NET have been burdened with multiple adverse side effects such as nausea (5), sexual dysfunction (6), increased suicide risk (7) for drugs that elevate 5-HT levels and elevated heart rate and blood pressure (8, 9) for drugs that increase noradrenaline levels. This makes a selective and potent DAT inhibitor, with a neurochemical profile distinct from that of stimulants, a highly desirable compound for the treatment of CNS disorders.
ADD and ADHD are neurodevelopmental psychiatric, behavioural and cognitive disorders characterised by concentration deficits, inner restlessness/hyperactivity, and impulsivity. These are the most common behavioural disorders amongst children, with a prevalence of 5-10% of the general population. It is widely believed that the symptoms of these disorders result from a dopaminergic and/or noradrenergic hypofunction. There is a wealth of information showing that the core symptoms of ADHD are influenced by changes in dopaminergic function (10) and hence a DAT inhibitor which would raise synaptic DA levels, should be efficacious. Current treatments for ADD/ADHD include the stimulants amphetamine and methylphenidate. These compounds have pharmacological activity for DAT, amongst other activities, and it is believed that their efficacy is derived from the elevation of corticostriatal DA and NE. These drugs are not selective DAT inhibitors however, and as such cause rapid, transient and marked release of DA from synaptic terminals which has been associated with their unwanted side effects, such as abuse potential. This neurochemical profile is distinct from that of a selective and potent DAT inhibitor which causes a slower increase in dopamine which is sustained for a much longer duration. This different neurochemical profile has been associated with less reinforcing effects and subsequently lower abuse potential (11). In addition to the neurochemical evidence for a likely therapeutic benefit of DAT inhibitors in ADHD, several studies have shown associations between DAT polymorphisms and overexpression of DAT in ADHD (12). Preclinical models of ADHD symptoms have shown that like amphetamine and methylphenidate a selective DAT inhibitor will decrease impulsive behaviour in rodents (13) further supporting the potential for efficacy of DAT inhibitors. Collectively this evidence provides compelling data to believe that selective DAT inhibitors will be efficacious in ADD/ADHD and other disorders characterised by poor impulse control (such as Trichotillomania, pathological gambling, Kleptomania and disorders with comorbid impulse control such as Parkinson's disease) or inattention.
Tourette's syndrome is a neuropsychiatric disorder characterised by motor and/or phonic tics. It normally presents during childhood and is poorly treated with drugs. Studies have postulated that one aspect underlying Tourette's is dopaminergic dysfunction whereby tonic/phasic dysfunction results in reduced synaptic DA levels and consequently higher levels in axon terminals leading to increased stimulus dependent release. Further studies have shown that post-mortem tissue from Tourette's patients showed elevated levels of DAT in the frontal lobe (14) and that polymorphisms in DAT are associated with the occurrence of Tourette's. This was further supported in a clinical study of drug naïve children which showed and increased specific/non-specific DAT binding ratio in those with Tourette's (15). These findings suggest that a selective DAT inhibitor may provide symptomatic relief for Tourette's patients.
Other neuropsychiatric disorders such as obsessive compulsive disorder (OCD), oppositional defiant disorder (ODD) and conduct disorder have also been associated with DAT. OCD patients have been shown to have an increased specific/non-specific DAT binding ratio (16) and this ratio was altered following treatment with SSRIs which are commonly used to treat OCD. Similarly abnormal dopamine function and/or dopamine turnover have been implicated in ODD, conduct disorder and other related behavioural disorders (17) and polymorphisms in DAT have been implicated as a risk factor for externalising behaviour in children. Studies showing that children with conduct disorder display disrupted reinforcement signalling and a response to reward have also suggested that modulation of synaptic dopamine levels could be a therapeutic option for these disorders presenting the opportunity to use a selective DAT inhibitor to treat these behavioural disorders.
Sleep disorders such as narcolepsy, cataplexy, excessive daytime sleepiness and shift work sleep disorder can interfere with an individual's normal mental and physical wellbeing. Several of these disorders are treated with drugs that have pharmacological activity at DAT. Modafinil is widely used to treat narcolepsy and its therapeutic potential has been related to occupancy of DAT). Other treatments for sleep disorders include amphetamine, methamphetamine and methylphenidate, all of which have pharmacological actions at DAT. Preclinical studies have shown that the wake promoting effects of several of these compounds and a selective DAT inhibitor are abolished in DAT knockout mice. Together these data support the use of a selective DAT inhibitor in the treatment of sleep disorders.
Mood disorders such as major depressive disorder, bipolar depression, seasonal affective disorder, melancholic depression, catatonic depression, postpartum depression and dysthymia represent a major medical and social burden on society and are amongst the most common of all CNS disorders. Treatment for these disorders is currently inadequate with low levels of efficacy and poor responder rates to currently available therapies. In addition many of the drugs that are the current standard of care carry unwanted side effects. SPECT studies in patients suffering from major depressive disorder have shown that there is an increased binding of DAT in depressed patients and that this was reversed following successful antidepressant treatment (18,19). In addition to this marketed antidepressants such as Nomifensine have a significant DAT inhibitory component to their mechanism of action. Preclinical studies investigating the behavioural phenotype of DAT knockout mice in tests for antidepressant activity have shown that genetic removal of DAT function results in antidepressant-like behaviour. This evidence is supportive for a therapeutic benefit for DAT inhibitors in mood disorders.
A comorbid symptom of depression and an unwanted side effect of many commonly used antidepressants is sexual dysfunction (20). Bupropion a commonly prescribed antidepressant with a significant DAT inhibitory component to its mechanism of action has been shown to result in fewer sexual dysfunction related side effects than other antidepressants (21). Furthermore Bupropion has been shown to reverse the sexual dysfunction caused by SSRIs. Preclinical studies have shown an effect of Bupropion on sexual behaviour in rats which is supported by clinical evidence that the drug is effective in treating women suffering from hypoactive sexual desire disorder. Amphetamine has also been shown to increase sexual behaviour in male and female rats and has also been shown to reverse sexual impairment in female rats. This evidence for drugs that have pharmacological activity at DAT is an indicator that a selective and potent DAT inhibitor would be a suitable therapy for antidepressant induced sexual dysfunction as well as for treating sexual dysfunction in non-depressed patients.
DAT polymorphisms have been implicated in anxiety disorders such as post traumatic stress disorder (PTSD) (22). The non-selective monoamine oxidase inhibitor Phenelzine which elevates dopamine levels in the brain amongst its actions has been shown to reduce the symptoms of PTSD. Bupropion which has a significant DAT inhibitory component to its mechanism of action is also prescribed for patients with anxiety disorders and has been shown to be efficacious in patients with panic disorder, further supporting the potential of DAT inhibitors in these conditions.
Movement disorders such as Parkinson's disease (PD) and Restless Leg Syndrome (RLS) are common neurological disorders which have been treated with therapies that result in elevated brain dopamine. PD is characterised by a loss of dopaminergic neurones in the nigrostriatal pathway and a subsequent loss of dopamine. Drugs such as L-DOPA which is converted to dopamine in the brain have been shown to alleviate the motor symptoms of both PD and RLS. Given that DAT inhibitors also increase dopamine levels it is reasonable to assume that they would also provide therapeutic benefit in movement disorders which have been shown to have a dopaminergic component. Further support for this hypothesis is given by the fact that methylphenidate, a stimulant which has DAT inhibition amongst its pharmacological activities has shown to be clinically efficacious in PD patients, both in motor (23) and non-motor symptoms (24,25).
Addiction and substance abuse are closely linked to dopamine and reward circuits in the brain. These substance dependencies include alcohol dependence, opioid dependence, cocaine dependence, cannabis dependence, amphetamine dependence (or amphetamine-like), hallucinogen dependence, inhalant dependence, polysubstance dependence, phencyclidine (or phencyclidine-like) dependence, and nicotine dependence. Preclinical studies using the selective DAT inhibitor GBR12909 and other benztropines have shown that these compounds can block the rewarding effects of drugs of abuse, such as cocaine. GBR12909 has been shown to block the neurochemical effects of cocaine (26, 27) as well as that of amphetamine. Furthermore compounds which have been demonstrated to be DAT inhibitors are effective in smoking cessation. This provides evidence that a high affinity, selective DAT inhibitor could block the rewarding effects of drugs of abuse and be an effective medication to treat addiction.
Dopamine is also known to have a role in eating disorders such as Binge Eating Disorder (BED). Eating disorders such as BED are known to have multiple components including impulse control, reward circuits and cognition, all of which are under the influence of dopaminergic signalling. It has been shown that BED sufferers have abnormal brain dopamine responses, which regulates motivation for food intake (28). In addition BED and obese patients show an abnormal frontostriatal dopamine signalling as compared to healthy controls (29). Preclinical models have shown that stimulation of the nucleus accumbens, which receives major dopaminergic input, attenuates binge eating behaviour in rats and that this effect is blocked by dopaminergic antagonists. This indicates that increased synaptic dopamine is a potential therapeutic opportunity for eating disorders such as binge eating disorder. Preclinical data has shown that food intake is modulated by drugs which modulate synaptic dopamine levels and specifically by compounds with affinity at DAT (30). DAT has been specifically implicated in BED and other eating disorders due to polymorphisms in DAT being associated with eating disorders (31). This hypothesis is further supported by the efficacy of drugs with DAT inhibition as part of their mechanism of action in clinical trials of BED and other eating disorders (32). Together this is supportive for the therapeutic potential of a selective DAT inhibitor in eating disorders such as BED.
Dopamine has a well-documented role in cognition and particularly in cognitive deficits seen in patients suffering from diseases characterised by abnormal dopaminergic signalling such as Parkinson's disease and schizophrenia (33). This coupled with the fact that cortical dopamine D1 receptor function is linked to NMDA mediated glutamate signalling implies that cognitive processes would be expected to be enhanced by DAT inhibitors.
Chronic or persistent fatigue is a symptom which is common to several diseases and can be persisting or relapsing (34). Disease states that are associated with fatigue include chronic fatigue syndrome, post-viral fatigue syndrome, HIV, multiple sclerosis, amyotrophic lateral sclerosis (ALS), myasthenia gravis, sarcoidosis, cancer, chemotherapy treatment, celiac disease, irritable bowel syndrome, spondyloarthropathy, fibromyalgia, arthritis, infectious diseases, diabetes, eating disorders, Parkinson's disease, sleep disorders, stroke, mood disorders, drug and alcohol abuse. Clinical studies have shown that multiple drugs with DAT inhibition as part of their mechanism of action are effective in combating fatigue in chronically ill patients (35). Drugs such as modafinil, methylphenidate and bupropion which share DAT inhibition as a common pharmacological mechanism of action have been shown to be efficacious in fatigue associated with cancer, chemotherapy, sarcoidosis, ALS, depression, bipolar disorder, multiple sclerosis, Parkinson's disease, HIV and chronic fatigue syndrome. This evidence is supportive of likely efficacy for a selective and potent DAT inhibitor in fatigue associated with the diseases mentioned above.
The multiple potential applications for a selective and potent DAT inhibitor have resulted in numerous chemical series being described in the literature. A particular issue has been pharmacological selectivity, with many previously described structural classes of DAT inhibitors suffering from significant off target pharmacology, which has limited their development. A particular issue is the affinity of DAT inhibitors described in the literature for ion channels. Vanoxerine has been shown to have significant activity at multiple ion channels resulting in a cardiovascular safety risk that has hampered its development (36). The compound showed potent functional activity at multiple sodium, calcium and potassium channels which would be an undesirable profile for a drug to treat CNS disorders. In addition to off target ion channel pharmacology DAT inhibitors (particularly those of the benztropine class) have been shown to have pharmacological activity at multiple other receptors such as the serotonin receptor 5-HT2, the muscarinic receptor M1 and the histamine receptor H1 (37,38,39). These significant secondary pharmacological activities may introduce unwanted side effects to potentially therapeutically beneficial DAT inhibitors. This makes the selectivity profile of DAT inhibitors of particular importance.
Therefore there remains a need to develop new DAT inhibitors, especially inhibitors that are selective over noradrenaline and serotonin, that will have utility to treat a wide range of disorders, in particular to treat depression, ADHD and eating disorders. Preferred compounds will possess a good pharmacokinetic profile and in particular will be suitable as drugs for oral delivery. Particularly preferred compounds will additionally display selectivity over noradrenaline and serotonin.